CN103221382A - Preparation of pet precursor - Google Patents
Preparation of pet precursor Download PDFInfo
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- CN103221382A CN103221382A CN2011800571229A CN201180057122A CN103221382A CN 103221382 A CN103221382 A CN 103221382A CN 2011800571229 A CN2011800571229 A CN 2011800571229A CN 201180057122 A CN201180057122 A CN 201180057122A CN 103221382 A CN103221382 A CN 103221382A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a process for preparation of radiopharmaceutical precursors, and in particular protected amino acid derivatives which are used as precursors for production of radiolabeled amino acids for use in in vivo imaging procedures such as positron emission tomography (PET). Particularly, the invention relates to a process for preparation of a precursor of the [18F]-1-amino-3- fluorocyclobutanecarboxylic acid ([18F] FACBC) PET agent and particularly to the work-up process of this precursor removing generated salts from the intermediate composition.
Description
The present invention relates to a kind of method that is used to prepare radiopharmaceutical precursors, particularly shielded amino acid derivative, it produces radiolabeled amino acid whose precursor with acting on, and is used for the in-vivo imaging program, for example positron emission tomography (PET).Particularly, the present invention relates to a kind of preparation [
18F]-1-amino-3-fluorine cyclobutane-carboxylic acid ([
18F] FACBC) aftertreatment of method, especially this precursor of precursor of PET reagent.
The multiple disease of PET efficient diagnosis comprises heart trouble and cancer.The nuclear medicine method relates to and gives the suitable radioisotopic reagent of patient's mark (" radiopharmaceuticals "), then detects by the direct or indirect gamma-radiation of emission of this reagent.These formation methods are favourable compared with other in-vivo imaging method, and to disease high degree of specificity and susceptibility, they also provide the functional information about infringement.For example, the PET radiopharmaceuticals [
18F] 2-fluoro-2-deoxy-D-glucose ([
18F] FDG) in the zone of glucose metabolism, concentrate, thus but make special detection wherein strengthen the tumour of glucose metabolism.Implement the nuclear medicine inspection by the radiopharmaceutic distribution that tracking gives, and the data based radiopharmaceutic character that obtains thus and becoming.Therefore, developed different radiopharmaceuticals and be used for multiple application, for example, tumour diagnostic reagent, blood flow diagnostic reagent and receptor mapping reagent.
In recent years, the amino-acid compound that has designed a series of radiohalogen-marks is as new radiopharmaceuticals, comprise [
18F]-1-amino-3-fluorine cyclobutane-carboxylic acid ([
18F] FACBC).Think [
18F] FACBC is effectively as the diagnostic reagent of highly breeding tumour, because it has the character that is absorbed by amino acid transport body specificity.
EP1978015 (A1) provide [
18F] the FACBC compound precursor and with the method for the described precursor of small-scale production.Flow process 1 be presented at describe among the EP1978015 be used for the preparation [
18F] FACBC synthetic:
Flow process 1
In above flow process 1, BnO represents benzylic ether, and Boc represents tertiary butyl carbamate, and OTf represents triflate.
Synthetic on the automated synthesiser unit [
18F] FACBC based on [
18F] fluorochemical is to the nucleophilic displacement from the trifluoromethanesulfonic acid ester group of formula V precursor.[
18F] fluorochemical can be incorporated into reaction vessel with the solution of kryptofix (K222), salt of wormwood, water and acetonitrile.
18The midbody compound of F-mark experiences two deprotection steps subsequently, and wherein ethyl and Boc blocking group are removed by alkalescence and acidic hydrolysis respectively.
The compound of formula III:
Called after 1-(N-(tert-butoxycarbonyl) amino)-3-benzyloxy-tetramethylene-1-carboxylic acid ethyl ester.According to flow process 1, this compound is by cis enantiomer preparation in multistep is synthetic of glycolylurea.In the aftertreatment of this intermediate, ethyl acetate and hydrochloric acid are joined in the resultant composition, extract organic layer subsequently, and wash with water.In this process of the compound for preparing formula III, produce salt.Produce so a large amount of salt, must before next step, they be removed.When with fairly large (for example technical scale for example, prepares the compound up to the 500 g formula IIIs) step 1 of implementing procedure 1 and reaction of 2, observe significant problem.When with fairly large enforcement, HCl and ethyl acetate joined in the crude reaction thing form emulsion, can not form the biphasic system of expectation.When with such mass preparation, because strainer is stopped up fully, it also is impossible utilizing the salt that removes by filter generation.
Therefore, need overcome the post-treating method of compound of the mass preparation formula III of these problems.
Now, be surprised to find that if add ethyl acetate in the crude compound of formula III, to form except the compound of formula III, also comprise the suspension of most of inorganic salt, this problem can be avoided.In addition, water joined form biphasic system in the suspension, this biphasic system will keep product in organic phase, and remaining salt is at aqueous phase.Separate two-phase and cause the compound of formula III to be retained in the organic phase, and inorganic salt abandon with water.
Because its lipophilic characteristic, the compound of formula III has the solubleness of non-constant at aqueous phase, therefore, when using method of the present invention to be used for this compound of purifying, does not observe the remarkable loss of compound.
Therefore, in a first aspect of the present invention, provide the post-treating method of the compound that is used for preparation formula IIIa:
Wherein:
R represents to have the alkyl of 1-5 carbon atom;
X represents the blocking group of alcohol;
Y represent amine blocking group and
Wherein said method comprises post-treating method, and described post-treating method may further comprise the steps:
I) provide the crude reaction product of the compound that comprises described formula III a;
Ii) ethyl acetate is joined step I) crude reaction product in, with prepare suspension;
Iii) water is joined step I i) suspension in, comprise the biphasic system of water and organic phase with formation, and abandon water;
Iv) acid is joined in the step I organic phase ii), comprise the biphasic system of acid water and organic phase, and abandon acid water with formation;
V) wash step I organic phase v) with water.
Each step is preferably carried out with the order that as above provides.
Term "
Post-treating method" get implication common in its this area, and be meant the required sequence of operations of product of separation and purifying chemical reaction.Under situation of the present invention, the product of chemical reaction is the compound of the formula III a of this paper definition.
Term "
Alkyl" alone or in combination, be meant to have general formula C
nH
2n+1The straight or branched alkyl.Such examples of groups comprises methyl, ethyl and sec.-propyl.
Term "
Blocking group" be that those skilled in the art are well-known.By chemically modified functional group, blocking group is introduced intramolecularly, so that in chemical reaction subsequently, obtain chemo-selective.The use of blocking group is described in ' Protective Groups in Organic Synthesis (blocking group in the organic synthesis) ', Theorodora W. Greene and Peter G. M. Wuts, (the 4th edition, John Wiley ﹠ Sons, 2007).
Herein term "
Alcohol" be meant the substituting group that comprises group-OH.
Herein term "
Amine" be meant group-NR'R'', wherein R' and R'' are hydrogen or alkyl independently, and preferably are hydrogen.
Herein term "
Crude reaction product" be meant the product of the chemical reaction before any step of carrying out post-treating method, wherein the term post-treating method as above defines.Particularly, in the context of the present invention, crude reaction product is meant the product (with the step 1 of above flow process 1 and 2 similar) that Y and R is joined the chemical reaction that compound carried out of formula Ia.These steps illustrate with step 1a and 2a following:
Step 1a:
Step 2a:
Wherein under each situation, X, R and Y such as this paper define for formula III a.
"
Provide" step (i) of described crude reaction product comprises the as above step 2a of explanation, and this step particular compound at formula III in embodiment 1 is described.This step comprises the compound that makes formula IIa and the protection reagent react of amine.The crude reaction product that comprises the compound of formula III a comprises salt.
Term "
Salt" be that those skilled in the art are well-known, and be meant the ionic compound that the neutralization by bronsted lowry acids and bases bronsted lowry obtains.When the compound of preparation formula IIIa, for example during the compound of formula (III), produce salt by the reagent and the intermediate of technological process.Such salt may comprise the salt of different chlorides, thionyl chloride for example, but this depends on the concrete reagent and the blocking group of use.
Term "
Suspension" get implication common in its chemical field, it is the inhomogeneous fluid that contains enough greatly with can settled solid particulate.By at step I i) in add ethyl acetate, be created in the solid particulate in the suspension of the present invention, ethyl acetate is used to make the salt precipitation to separate out.
The term that uses (iii) and (iv) in step "
Biphasic system" be meant the biphasic system that comprises water and organic phase.The term that uses in (iii) in step "
Water" be meant and comprise as the water soluble ingredient of the water of solvent and biphasic system mutually.Step use (iii) and (iv) "
Organic phase" be meant and comprise ethyl acetate and the component that dissolves in biphasic system wherein mutually.The term that uses in (iv) in step "
Acid water" be meant the phase of biphasic system, comprise acid and dissolve in the component of the biphasic system of step I v wherein.
Step (iv) "
Acid" be mineral acid, and should select to make it not influence blocking group X and Y.Acid is preferably hydrochloric acid (HCl), or other mineral acid of identical pKa is provided.
Part R is the straight or branched alkyl chain, and is preferably the alkyl that is selected from methyl, ethyl, 1-propyl group or sec.-propyl, most preferably ethyl.
X partly is the blocking group of alcohol; select blocking group to make blocking group form its relevant ether; for example, benzyl (Bn); methoxymethyl (MOM); 2-methoxy ethoxy methyl (MEM); methylthiomethyl (MTM); THP trtrahydropyranyl (THP); benzyloxymethyl (BOM); p-methoxyphenyl; to methoxy-benzyl (MPM); to methoxyl group benzyloxy ylmethyl (PMBM); triisopropyl silyl (TIPS); t-butyldimethylsilyl (TBDMS); 2-(trimethyl silyl) ethoxyl methyl (SEM) and (phenyl dimetylsilyl) methoxymethyl (SMOM).The preferred group that can remove by hydrogenation, in preferred embodiments, X is a benzyl.
Y partly is the blocking group of amine, for example carbamate.Preferred Y is selected from tertiary butyl carbamate (Boc), 9-fluorenyl (fluoroenyl) methyl carbamate (Fmoc), methyl carbamate, ethyl carbamate, 2-chloro-3-indenyl methyl carbamate (Climoc), benzo [f] indenes-3-ylmethyl carbamate (Bimoc), 2,2,2-trichlorine ethyl carbamate (Troc), 2-chloroethyl amino manthanoate, 1,1-dimethyl-2,2-dibromo ethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichlorine ethyl carbamate (TCBOC), benzylamino manthanoate (Cbz) and diphenyl methyl carbamate.Most preferably Y is a tertiary butyl carbamate, so that N-to be provided tert-butoxycarbonyl.
In particularly preferred embodiments, R is an ethyl, and X is a benzyl, and Y is Boc, makes that the compound of formula III a is the compound of formula III.
The step of described method (ii) in, ethyl acetate is joined in the composition of the crude compound that comprises formula III a.Compare with the material quantity of the reaction of preparation formula IIIa crude compound, the ethyl acetate amount of adding is for example 15:1-25:1, and more preferably 18:1-21:1 is in volume/weight %.In a preferred embodiment, raw material is defined as the compound compositions that comprises formula IIa.Such composition also can comprise salt.When adding ethyl acetate, form suspension.In this step, do not add acid.If described in EP1978015, add acid, when with fairly large carrying out, will form emulsion in this stage.
Step (iii) in, water is joined in the step suspension (ii), desalt to remove.If in the crude compound of formula III a, add entry, be dissolved in aqueous phase to guarantee most of inorganic salt, producing relevant problem with salt so can be avoided, and salt is transferred to aqueous phase, and it is abandoned.The compound of formula III a is still stayed in the organic phase, does not have salt, and this will exist mutually at last handling process.Compare with the material quantity of the reaction of the crude compound of preparation formula IIIa, the water yield that adds in (iii) in step is for example 5:1-15:1, and more preferably 9:1-10:1 is in volume/weight %.Most preferably, the water yield that step adds in (iii) be step (ii) in adding the ethyl acetate amount pact half.
Step (iv) in, acid is joined in the step organic phase (iii).When adding acid, another takes place be separated, and form the biphasic system that comprises organic phase and acid water.Water is abandoned, and organic phase proceeds to post-treating method.The function of acid is to make the target compound of formula III a protonated, exists with the compound of anionic type to avoid this compound, and the compound of anionic type will be extracted into aqueous phase.The amount of acid be preferably with step (ii) in the roughly the same amount of ethyl acetate amount of adding, and concentration is for example 0.2-0.8 volumetric molar concentration, most preferably 0.5 volumetric molar concentration.
(v), comprise the washing with water from step organic phase (iv) of compound of formula III a, preferred washing for several times in step.This washing step can comprise the aqueous solution and the salt water washing with pure water, sodium bicarbonate.Preferably, this step comprises and washes twice with water, then with the solution washing of sodium bicarbonate, then washes with water once more, uses the step of salt water washing subsequently.Wash with water each time preferably and carry out twice.In a preferred embodiment, (v) comprise the plurality of washing step, use given water content each time, preferably wash twice with water, the solution washing with sodium bicarbonate washes with water this washing step once more, uses the salt water washing subsequently.For all these steps, given water content is preferably identical, and water content is preferably identical with the water yield that adds in (iii) in step.
In post-treating method of the present invention, separating each time by extraction of organic phase and water undertaken.
(v), optional other step comprises and for example concentrates under reduced pressure that (composition v) for example uses suitable siccative to be dried and for example by sudden strain of a muscle formula chromatography purifying on silicagel column from step in step.In a preferred embodiment, the compound for preparing formula III according to this method.
When with mass preparation, for example when the compound of the formula III a of preparation 100 g or more (for example 300 g, perhaps up to 500 g or more), method of the present invention is particularly useful.In on a small scale, the salt of generation can be by removing by filter, and still when scaling up, experience is, because the obstruction of strainer, can not be by removing by filter salt.Discovery comprises that washing removes simpler and the more effective and cost-effective of method of the present invention that desalts.When scaling up,, find that further described method is less consuming time compared with the method that comprises the salt that filtering produces.The method that comprises filtering salt (if possible) with use is compared, and expection is saved 2-4 days when with extensive use method of the present invention.If attempt to comprise the method for filtering salt, needs are used for the equipment of extensive filtering costliness with extensive use.
In a preferred embodiment, be used for the starting composition of post-treating method of the present invention, that is, comprise the composition of crude compound IIIa, comprise the cis of compound III a (the more especially compound of formula III)-and the mixture of trans-enantiomer.Therefore, in a preferred embodiment, the initial reagent that is used for the method for flow process 1 is the cis of the glycolylurea of formula 0-and the mixture of trans-enantiomer:
It is 5-(3-benzyloxy tetramethylene) glycolylurea.
When using method of the present invention, find in preparation
18In any stage of the process of the precursor of F-FACBC (in flow process 1, being called compound V), do not need initiatively to separate enantiomer.
In yet another aspect, the invention provides a kind of method that is used for the compound of preparation formula Va:
Wherein Y and R are suitable and preferably define for formula III a as this paper and LG is a leavings group;
Wherein said method comprises the compound according to suitable and preferred method preparation formula IIIa as defined herein.
Leavings group LG be preferably halogenic substituent or-OR
2The group of expression, wherein R
2Be fluosulfonic acid substituting group or aromatic sulfonic acid substituting group.Most preferably leavings group is selected from toluenesulphonic acids substituting group, nitrobenzene-sulfonic acid substituting group, Phenylsulfonic acid substituting group, trifluoromethanesulfonic acid substituting group, fluosulfonic acid substituting group or perfluoro alkyl sulfonic acid substituting group.
The compound of formula Va is preferably the compound of formula V:
?(V)
It is
18The direct labelled precursor compound of F-FACBC.OTf represents triflate.Y then is Boc in formula IIa, and R is an ethyl.
In another embodiment again, the invention provides a kind of method that is used for the compound of preparation formula VI:
Wherein said method comprises the compound according to suitable and preferred method preparation formula IIIa as defined herein.
Illustrate the present invention by following examples.
Synthetic and the purifying of embodiment 1:1-(N-(tert-butoxycarbonyl) amino)-3-benzyloxy-tetramethylene-1-carboxylic acid ethyl ester (compound of formula (III)).
Synthetic:
Under nitrogen atmosphere, 1-amino-3-benzyloxy tetramethylene-1-carboxylic acid ethyl ester (compound of formula II) (630 g comprise the salt resistates from preceding step) is stirred in ethanol (18500 ml) and triethylamine (2000 ml), and be cooled to＜5 ℃.In refrigerative solution, add the two carbonic acid tert-butyl esters (602 g), make resulting mixture reach envrionment temperature and stirred 20 hours, analyze the monitoring reaction process by TLC simultaneously.After reaction is finished, mixture is extremely done 35 ℃ of following vacuum-evaporation.
Purifying:
To compound that comprises formula III and salt from above synthetic crude product in add ethyl acetate (12000 ml), to obtain suspension, (6000 ml) joins in the suspension with water, to form biphasic system.To respectively be separated, water will be abandoned.Organic phase abandons acid water with HCl (12000 ml, 0.5 M) washing.Organic phase water (6000 ml, * 2) is followed sodium hydrogen carbonate solution (6000 ml), water (6000 ml) and salt solution (6000 ml, * 2) washing, and organic phase is filtered through anhydrous sodium sulfate drying, and vacuum-evaporation is to provide title compound.
Claims (15)
1. method that is used for the compound of preparation formula IIIa:
Wherein:
R represents to have the alkyl of 1-5 carbon atom;
X represents the blocking group of alcohol;
Y represent amine blocking group and
Wherein said method comprises post-treating method, and described post-treating method may further comprise the steps:
I) provide the crude reaction product of the compound that comprises described formula III a;
Ii) ethyl acetate is joined step I) crude reaction product in, with prepare suspension;
Iii) water is joined step I i) suspension in, comprise the biphasic system of water and organic phase with formation, and abandon water;
Iv) acid is joined in the step I organic phase ii), comprise the biphasic system of acid water and organic phase, and abandon acid water with formation;
V) wash step I organic phase v) with water.
2. the process of claim 1 wherein that X is a benzyl.
3. the method for claim 1 or claim 2, wherein R is an ethyl.
4. each method among the claim 1-3, wherein Y is tertiary butyl carbamate (Boc).
5. each method among the claim 1-4 is wherein at step I i) in, to compare with the material quantity of the compound that comprises formula IIa, the ethyl acetate amount of adding is 15:1-25:1, in volume/weight %
Wherein X and R such as claim 1 definition.
6. each method among the claim 1-5, wherein step I ii) in, the water yield of adding is at step I i) in the ethyl acetate amount that adds pact half.
7. each method among the claim 1-6, wherein step I v) in, the acid of adding is HCl.
8. each method among the claim 1-7, wherein step I v) in, washing comprises the aqueous solution and the salt water washing of using pure water, sodium bicarbonate.
9. each method among the claim 1-8, described method also comprise under reduced pressure concentrating and derive from step I composition v), the step of dry and purifying.
10. each method among the claim 1-9, wherein said crude reaction product comprise the cis of formula III a compound-and the mixture of trans-enantiomer.
11. method that is used for preparation formula V compound:
Wherein Y such as claim 1 or claim 4 definition, R such as claim 1 or claim 3 definition and LG be leavings group;
Wherein said method comprises the compound according to each method preparation formula IIIa among the claim 1-10.
12. the defined method of claim 11, wherein said leavings group be halogenic substituent or-OR
2The group of expression, wherein R
2Be fluosulfonic acid substituting group or aromatic sulfonic acid substituting group.
13. the defined method of claim 12, wherein said leavings group are selected from toluenesulphonic acids substituting group, nitrobenzene-sulfonic acid substituting group, Phenylsulfonic acid substituting group, trifluoromethanesulfonic acid substituting group, fluosulfonic acid substituting group or perfluoro alkyl sulfonic acid substituting group.
14. the defined method of claim 11 or claim 12, the compound of wherein said formula Va are the compound of formula V:
15. method that is used for preparation formula VI compound:
Wherein said method comprises the compound according to each defined method preparation formula IIIa among the claim 1-10.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41749010P | 2010-11-29 | 2010-11-29 | |
| US61/417,490 | 2010-11-29 | ||
| US61/417490 | 2010-11-29 | ||
| PCT/EP2011/071145 WO2012072567A1 (en) | 2010-11-29 | 2011-11-28 | Preparation of pet precursor |
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| Publication Number | Publication Date |
|---|---|
| CN103221382A true CN103221382A (en) | 2013-07-24 |
| CN103221382B CN103221382B (en) | 2016-06-01 |
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| CN201180057122.9A Expired - Fee Related CN103221382B (en) | 2010-11-29 | 2011-11-28 | Preparation pet precursor |
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|---|---|
| US (1) | US9278916B2 (en) |
| EP (1) | EP2646411B1 (en) |
| JP (1) | JP6018578B2 (en) |
| KR (1) | KR20130140041A (en) |
| CN (1) | CN103221382B (en) |
| AU (1) | AU2011335084B2 (en) |
| CA (1) | CA2820363A1 (en) |
| DK (1) | DK2646411T3 (en) |
| ES (1) | ES2643500T3 (en) |
| MX (1) | MX2013006050A (en) |
| NO (1) | NO2646411T3 (en) |
| RU (1) | RU2587308C2 (en) |
| WO (1) | WO2012072567A1 (en) |
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| GB201214220D0 (en) * | 2012-08-09 | 2012-09-19 | Ge Healthcare Ltd | Radiosynthesis |
| CN114767929A (en) * | 2022-03-14 | 2022-07-22 | 上海理工大学 | Communicated porous PHBHHx bone filling microsphere material and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101443307A (en) * | 2006-05-11 | 2009-05-27 | 日本医事物理股份有限公司 | Method for preparing radioactive fluorine labeled organic compound |
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| JP3325225B2 (en) * | 1998-04-20 | 2002-09-17 | 株式会社トクヤマ | Method for producing N-hydrocarbon oxycarbonyl amino acid ester |
| PT1978015T (en) * | 2005-11-29 | 2018-03-26 | Nihon Mediphysics Co Ltd | Precursor compound of radioactive halogen labeled organic compound |
| CA2672914C (en) | 2006-12-27 | 2014-02-04 | Nihon Medi-Physics Co., Ltd. | Process for production of precursor compound for radioactive halogen-labeled organic compound |
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2011
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101443307A (en) * | 2006-05-11 | 2009-05-27 | 日本医事物理股份有限公司 | Method for preparing radioactive fluorine labeled organic compound |
Non-Patent Citations (1)
| Title |
|---|
| 张兴忠等: "β-榄香烯醇酯类化合物的合成及抗癌活性研究", 《中国药物化学杂志》 * |
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| JP2014506236A (en) | 2014-03-13 |
| EP2646411B1 (en) | 2017-08-16 |
| EP2646411A1 (en) | 2013-10-09 |
| US9278916B2 (en) | 2016-03-08 |
| ES2643500T3 (en) | 2017-11-23 |
| WO2012072567A1 (en) | 2012-06-07 |
| CA2820363A1 (en) | 2012-06-07 |
| KR20130140041A (en) | 2013-12-23 |
| CN103221382B (en) | 2016-06-01 |
| MX2013006050A (en) | 2013-06-28 |
| RU2013122655A (en) | 2015-01-10 |
| AU2011335084B2 (en) | 2015-08-20 |
| DK2646411T3 (en) | 2017-10-16 |
| AU2011335084A1 (en) | 2013-07-04 |
| JP6018578B2 (en) | 2016-11-02 |
| RU2587308C2 (en) | 2016-06-20 |
| US20130245307A1 (en) | 2013-09-19 |
| NO2646411T3 (en) | 2018-01-13 |
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